Implant devices, for example stents, can be used when the lumen of an artery undergoes a narrowing, for example provoked by an obstruction. Such obstruction results in decreased blood flow and can cause ischemic phenomena.
A stent is a cylindrical metallic structure that is introduced into the artery lumen and made to expand at the level of the obstruction until its diameter is equal to the original diameter of the vessel. In this way the vessel narrowing, i.e., stenosis, is reduced, both in the acute phase and in the long term.
Through the years, the principal function of the stent, as mechanical support of the vessel, was joined by a pharmacologic action to reduce the incidence of a phenomenon known as restenosis, which consists of partial or total reocclusion of the vessel.
The phenomenon is attributed essentially to the undesired proliferation of smooth muscle cells in the vessel walls that can be triggered by factors attributable to the procedural phase (excessive stress to the vessel wall) and/or to the implanted device (reduced biocompatibility of materials, suboptimal surface characteristics, excessive structural rigidity, etc.).
The association of active principles to implant devices with the object of limiting restenosis is an established technique
Typical examples are the so-called Drug Eluting Stents (DESs), i.e., stents that carry pharmaceutical substances, such as agents that are antagonistic to restenosis, to the stent implantation site.
An active principle can be loaded onto implantable devices by means of compounds that act as vectors for them and that modulate their delivery in correspondence to the implantation site.
Although polymeric constituents have been used as vectors for delivery of active principles from, for example, coronary stents, several reasons for concern have now been raised regarding the safety of these materials.
For example, polymeric substances applied to an implantable device can remain in situ for very long periods of time, in this way disturbing or modifying the healing process at the implantation site in an undesirable way. This effect can be aggravated by incomplete delivery of the drug by the vector.
Such adverse reactions remain also when biodegradable polymers are used. In fact, the polymer always remains beyond the period of diffusion of the active principle and introduces the possibility of cytotoxic or inflammatory effects linked to in situ degradation of the polymeric vector (take, for example, the degradation of polyester-based polymers).
Compositions that are not polymeric in nature have been used for delivery of active principles, for example in the form of fatty acid esters of polyalcohols, sugars or vitamins as described in the European patent application EP-A-1 994 950.
The compositions described in EP-A-1 994 950 have been shown capable of regulating delivery of active principles by implanted devices and to avoid the long-term negative biological effects linked to the presence of polymeric vectors on the device itself.
Nevertheless, these solutions are not always satisfactory in terms of optimal modulation of active principle delivery by implanted devices and of applicability to the preparation of molecules particularly subject to degradation during the manufacturing process of the implantable device. In fact, the use of drugs that are extremely potent from a pharmacological point of view (e.g., antitumor or immunosuppressive drugs) require controlled delivery of the active principle that is prolonged over time, to prevent and/or reduce vessel restenosis, and that is very accurate also in the early phase of administration, controlling possible initial peaks of drug to avoid local toxic effects. On the other hand, the scarce stability of some drugs requires that the most gentle preparative conditions (temperature, mechanical stress, solvents, etc.) possible be used and therefore that suitable compositions are chosen for their loading on implant devices, for example stents.